CD38 Molecule (CD38)

.infobox .infobox-gene { ^{1(2015) CD38 in neuroinflammation2015 · Adv Exp Med Biol · PMID 26369749Open reference} float: right; ^{2(2015) Alzheimer disease pathology as a host response2015 · Nat Neurosci · PMID 26117742Open reference} width: 300px; ^{3(2019) CD38 in neurodegenerative diseases2019 · J Neurochem · PMID 31490623Open reference} padding: 10px; ^{4(2016) CD38 and its role in the brain2016 · Adv Exp Med Biol · PMID 27572028Open reference} background: #f8f9fa; ^{5(2003) CD38 as a therapeutic target2003 · Mol Med · PMID 15175742Open reference} border: 1px solid #ddd; ^{6(2019) CD38 and calcium signaling in immune cells2019 · Curr Opin Immunol · PMID 31063967Open reference} border-radius: 4px; ^{7(2019) CD38 in age-related neurodegeneration2019 · Aging Cell · PMID 31141273Open reference} margin: 10px; ^{8(2020) CD38 in Alzheimer's disease2020 · J Alzheimers Dis · PMID 32568176Open reference} } ^{9(2016) CD38 on hippocampal neurons2016 · J Neurochem · PMID 27502959Open reference}

.infobox .infobox-gene th ^{10(2018) HIV-associated neurocognitive disorder and CD382018 · J Neurovirol · PMID 29766458Open reference} { background: #007bff; color: white; padding: 8px; }

.infobox .infobox-gene td { padding: 6px; }

Overview

CD38 is a transmembrane glycoprotein that functions as both an ecto-enzyme and a receptor. It catalyzes the synthesis and hydrolysis of cyclic ADP-ribose (cADPR), a key calcium-mobilizing second messenger. CD38 is expressed in various tissues including brain cells (neurons, astrocytes, microglia) and plays important roles in neuroinflammation, synaptic plasticity, and neurodegeneration^{2(2015) Alzheimer disease pathology as a host response2015 · Nat Neurosci · PMID 26117742Open reference}0.

Introduction

CD38 (gene symbol: CD38) is a type II transmembrane protein originally identified as a surface marker on hematopoietic cells. In the brain, CD38 is expressed in neurons and glial cells, where it regulates intracellular calcium levels through its enzymatic activity^{2(2015) Alzheimer disease pathology as a host response2015 · Nat Neurosci · PMID 26117742Open reference}1.

Gene and Protein Structure

The CD38 gene (Gene ID: 933) is located on chromosome 4p15.32 and encodes a protein of 301 amino acids. The CD38 protein structure consists of:

• N-terminal cytoplasmic tail: 20 amino acids

• Single transmembrane helix: anchors protein to membrane

• C-terminal extracellular domain: contains the enzymatic active site with a conserved His-X-Arg-Xaa-Ser motif

CD38 exists as a homodimer on the cell surface and undergoes conformational changes upon ligand binding^{2(2015) Alzheimer disease pathology as a host response2015 · Nat Neurosci · PMID 26117742Open reference}2.

Normal Function

Calcium Signaling

CD38 is the primary enzyme responsible for synthesizing cADPR from NAD⁺ in mammalian cells. cADPR acts as a potent second messenger that releases calcium from intracellular stores (endoplasmic reticulum) through ryanodine receptors^{2(2015) Alzheimer disease pathology as a host response2015 · Nat Neurosci · PMID 26117742Open reference}3.

NAD⁺ Metabolism

CD38 contributes to cellular NAD⁺ consumption and regulates NAD⁺/NADH ratios, affecting metabolic processes and sirtuin activity^{2(2015) Alzheimer disease pathology as a host response2015 · Nat Neurosci · PMID 26117742Open reference}4.

Immune Modulation

In immune cells, CD38 regulates cytokine production, phagocytosis, and cell proliferation through calcium-dependent signaling^{2(2015) Alzheimer disease pathology as a host response2015 · Nat Neurosci · PMID 26117742Open reference}5.

Brain Functions

• Social recognition memory: CD38-deficient mice show impaired social memory

• Glial function: Regulates microglial activation and astrocyte calcium signaling

• Synaptic plasticity: Influences hippocampal LTP through cADPR-mediated calcium release

Role in Alzheimer’s Disease

CD38 plays complex roles in AD pathogenesis:

Neuroinflammation

CD38 is upregulated in AD brain tissue and promotes inflammatory responses in microglia through enhanced calcium signaling and cytokine production^{2(2015) Alzheimer disease pathology as a host response2015 · Nat Neurosci · PMID 26117742Open reference}6.

NAD⁺ Depletion

AD brains show reduced NAD⁺ levels, partially due to CD38 overexpression. This affects sirtuin activity (particularly SIRT1) and mitochondrial function^{2(2015) Alzheimer disease pathology as a host response2015 · Nat Neurosci · PMID 26117742Open reference}7.

Amyloid Pathology

CD38 deficiency in APP/PS1 mice reduces amyloid plaque load and improves cognitive function, suggesting pathogenic role of CD38 in AD^{2(2015) Alzheimer disease pathology as a host response2015 · Nat Neurosci · PMID 26117742Open reference}8.

Therapeutic Potential

• CD38 inhibitors: Reduce neuroinflammation and amyloid pathology in preclinical models

• NAD⁺ boosters: May compensate for CD38-mediated NAD⁺ depletion

• Apigenin: Natural compound that inhibits CD38, under investigation for AD^{2(2015) Alzheimer disease pathology as a host response2015 · Nat Neurosci · PMID 26117742Open reference}9

Role in Neuroinflammation

CD38 regulates neuroinflammatory responses through multiple mechanisms:

Microglial Activation

CD38 expression increases in activated microglia, driving production of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6)^{3(2019) CD38 in neurodegenerative diseases2019 · J Neurochem · PMID 31490623Open reference}0.

Astrocyte Function

CD38 in astrocytes mediates calcium waves and ATP release, affecting neuroinflammatory cascades^{3(2019) CD38 in neurodegenerative diseases2019 · J Neurochem · PMID 31490623Open reference}1.

T Cell Communication

CD38 on CNS-infiltrating T cells modulates neuroinflammatory responses in autoimmune and degenerative conditions^{3(2019) CD38 in neurodegenerative diseases2019 · J Neurochem · PMID 31490623Open reference}2.

HIV-Associated Neurocognitive Disorder

CD38 is upregulated in HIV-infected macrophages and microglia, contributing to chronic neuroinflammation and neuronal dysfunction in HAND patients^{3(2019) CD38 in neurodegenerative diseases2019 · J Neurochem · PMID 31490623Open reference}3.

Therapeutic Targeting

CD38 Inhibitors

• Apigenin: Flavonoid CD38 inhibitor, neuroprotective in AD models

• Nucleoside analogs: Synthetic inhibitors in development

• 78c: Potent CD38 inhibitor with brain penetration

NAD⁺ Restoration

• Nicotinamide riboside (NR): NAD⁺ precursor that bypasses CD38

• Nicotinamide mononucleotide (NMN): NAD⁺ booster under investigation

Interactions

CD38 interacts with multiple proteins and pathways:

• Ryanodine receptors (RyR): Target of cADPR-mediated calcium release

• SIRT1: NAD⁺-dependent deacetylase regulated by CD38 activity

• PARP: Competes for NAD⁺ substrate

• Aquaporin-4: Modulates astrocytic water and calcium dynamics

Background

The study of Cd38 Molecule (Cd38) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

External Links

• NCBI Gene

• UniProt

• PubMed